The present invention relates to an indomethacin-containing transdermal absorption preparation.
Preparations for external use, containing anti-inflammatory analgesics, such as indomethacin more effective than salicylic drugs, have been used as one of therapeutic drugs in the treatment of pain due to contusion, sprain or muscular fatigue, and pain associated with shoulder stiffness. These preparations have been useful in that they diminish systemic adverse reactions because of topical administration. However, the percutaneous absorption of indomethacin is not sufficient, so that indomethacin-containing transdermal absorption preparations hitherto used have been solutions. The solution type indomethacin is easily hydrolyzable and lacks stability.
Indomethacin exists as xcex1-form (needle-like), xcex2-form, or xcex3-form (platy) crystals because of polymorphism. The xcex3-form is known as a stable form and the xcex1-form as a meta-stable form. The conventional commercially available transdermal indomethacin preparations have contained the solution type indomethacin or the xcex3-form crystals, and there have been no transdermal indomethacin preparations containing xcex1-form crystals. Rectal absorption from suppositories containing xcex1-form crystals of indomethacin has been reported to be better than that from suppositories containing xcex3-form crystals (T. Yokoyama, Journal of the Pharmaceutical Society of Japan, 99, 837-842, 1979), but there have been no studies of the absorption of transdermal absorption preparations containing xcex1-form crystals of indomethacin. Nor have there been any reports of the relationship between the crystal form of indomethacin and the stability of indomethacin in its preparations for external use.
It is an object of the present invention to provide an indomethacin-containing transdermal absorption preparation increased in the percutaneous absorption of indomethacin from the preparation, and improved in the stability of indomethacin in the preparation.
As a result of extensive studies in an attempt to solve the above-described problems, the inventors of this invention found that when indomethacin exists as xcex1-form crystals in a vehicle of a transdermal absorption preparation, its percutaneous absorption could be increased, and the stability of indomethacin could also be improved. This finding led them to accomplish the invention.
That is, the invention relates to a transdermal absorption preparation containing xcex1-form crystals of indomethacin in a vehicle.
In the invention, indomethacin may be present as xcex1-form crystals in the vehicle. In other words, it is not absolutely necessary to use xcex1-form crystals of indomethacin as a raw material for the preparation. Instead, a powder of indomethacin, or indomethacin in any of the three crystal forms may be used as a raw material for the preparation. Nor is it necessary for all of indomethacin to exist as xcex1-form crystals in the vehicle.
The dosage form of the transdermal absorption preparation that achieves the effect of the invention includes, for example, a liquid, a cream, an ointment, a gel, a patch, and an aerosol. However, these dosage forms are not limitative, and any dosage form usually applicable to the integument can be used.
To make indomethacin existent as xcex1-form crystals in the vehicle, particular conditions are required. That is, the pH of the vehicle, the amount of water blended, the type and amount of addition of a solvent for suspending indomethacin, the amount of indomethacin incorporated, the temperature during production, the rate of stirring during mixing, and the viscosity of the vehicle are of importance. Especially, the pH of the vehicle, the amount of water blended, the type and amount of addition of the solvent, and the amount of indomethacin incorporated are important.
The pH of the vehicle is 3.5 to 5.5, preferably 4.0 to 5.0. At pH of lower than 3.5, xcex3-form crystals are liable to occur. At pH of higher than 5.5, the amount of indomethacin dissolved increases, thus making it difficult to obtain xcex1-form crystals.
The amount of water blended is 30 to 90% by weight, preferably 40 to 80% by weight, in the vehicle. If the amount of water blended is less than 30% by weight, the amount of indomethacin dissolved in the solvent will increase. If the amount of water blended is more than 90% by weight, xcex3-form crystals are liable to occur, thus making it difficult to obtain xcex1-form crystals.
There is no limitation on the solvent for suspending indomethacin. Its examples are ethanol, propanol, isopropanol, propylene glycol, butylene glycol, polyethylene glycol, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene glycol fatty acid ester, polyoxyethylene polyoxypropyl alkyl ether, polyoxyethylene glycol ether, sorbitan fatty acid ester, and glycerin fatty acid ester. These solvents can be used alone or in combination of two or more. Preferably, propanol, isopropanol, propylene glycol, butylene glycol, and polyethylene glycol can be used alone or in combination of two or more. The amount of the solvent incorporated is 1 to 30% by weight, preferably 5 to 25% by weight, in the vehicle. If the amount of the suspending solvent incorporated is less than 1% by weight, xcex3-form crystals are liable to occur. If this amount is more than 30% by weight, the amount of indomethacin dissolved in the solvent increases, thus making it difficult to obtain xcex1-form crystals.
In addition to the amount of water incorporated in the vehicle and the amount of the suspending solvent incorporated in the vehicle, the mixing ratio of the water and the suspending solvent is important. If expressed as the weight ratio, the mixing ratio is 70:30 to 95:5, preferably 80:20 to 90:10. At a mixing ratio of 70:30 to 95:5, xcex1-form crystals of indomethacin are easy to be obtained.
The amount of indomethacin incorporated is 1 to 40% by weight, preferably 2 to 20% by weight, based on the suspension, and 0.1 to 2% by weight, preferably 0.3 to 1% by weight, in the vehicle. If the amount of indomethacin incorporated is less than 1% by weight based on the suspension, and less than 0.1% by weight in the vehicle, the dissolution rate of indomethacin increases. If the amount of indomethacin incorporated is more than 40% by weight based on the suspension, and more than 2% by weight in the vehicle, xcex3-form crystals are liable to occur, thus making it difficult to obtain xcex1-form crystals.
The temperature during production of the vehicle is 5xc2x0 C. or higher, preferably 10xc2x0 C. or higher. If the temperature is lower than 5xc2x0 C., the solubility of indomethacin in the vehicle declines, and xcex3-form crystals are liable to occur, thus making it difficult to obtain xcex1-form crystals.
The stirring rate during mixing differs according to the type of a mixer. When a biaxial kneader is used, for example, the rotational speed of the kneader is 5 to 100 revolutions/min, preferably 10 to 80 revolutions/min. At a kneader rotational speed of 5 to 100 revolutions/min, xcex1-form crystals of indomethacin are easy to be obtained.
The viscosity of the vehicle in a 10% aqueous solution is 2,000 cps or lower, preferably 1,000 cps or lower. At a viscosity of more than 2,000 cps, the degree of freedom of indomethacin in the adhesive mass declines, thus making it difficult to obtain xcex1-form crystals. Furthermore, the diffusion rate of dissolved indomethacin in the vehicle decreases, thus making it difficult to achieve satisfactory percutaneous absorption.
Water-soluble polymers, which can be added, where necessary, to the transdermal absorption preparation of the invention, include, for example, naturally occurring polymers, such as gelatin, alginate, corn starch, tragacanth gum, casein, and pectin; semisynthetic polymers, such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, dextrin, and carboxymethyl starch; synthetic polymers, such as polyvinyl alcohol, sodium polyacrylate, methoxyethylene maleic anhydride copolymer, polyvinyl ether, polyvinyl pyrrolidone, carboxyvinylpolymer, and polyacrylic acid. These polymers can be used alone or as a mixture of two or more. The amount of the any of these water-soluble polymers incorporated in the preparation is 30% by weight or less, preferably 15% by weight or less. If this amount is more than 30% by weight, it will become difficult to maintain the form of the preparation.
In the transdermal absorption preparation of the invention, the following synergists may be incorporated, where necessary, in addition to the above-mentioned ingredients: Salicylic esters, such as methyl salicylate, and glycol salicylate, ibuprofen, azulene, azulene sulfonate sodium, glycyrrhetic acid, and glycyrrhizin, as anti-inflammatory analgesics; diphenhydramine, and chlorpheniramine maleate, as antihistaminics; capsicum and its extract, nonylic vanillylamide, and benzyl nicotinate, as rubefacients; ethyl aminobenzoate, lidocaine, and dibucaine, as local anesthetics; tocopherol acetate, biotin, and vitamin B complex, as vitamins; camphor, menthol, and mentha oil, as refreshing agents; and ginger, zingiber siccatum, paeoniae radix, ginseng, angericae radix, and other extracts, as vegetable and animal drug ingredients. In addition, vehicle components or the like, which are usually used to obtain desired dosage forms, can be incorporated.
As means for making indomethacin present as xcex1-form crystals in the vehicle, the addition of a suspension of indomethacin to a water-soluble gel is cited as an example in the case of a patch. The water-soluble gel used here is not limited, if it is one which is crosslinkable, which is formed from a gelable, water-soluble polymer, and which has moderate stickiness depending on external conditions such as temperature. Examples of the water-soluble polymer are naturally occurring polymers, such as gelatin, alginate, corn starch, tragacanth gum, casein, and pectin; semisynthetic polymers, such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, dextrin, and carboxymethyl starch; synthetic polymers, such as polyvinyl alcohol, sodium polyacrylate, methoxyethylene maleic anhydride copolymer, polyvinyl ether, polyvinyl pyrrolidone, carboxyvinylpolymer, and polyacrylic acid. These polymers can be used alone or in combination of two or more. To the resulting vehicle, water-soluble polymers other than those mentioned above, stabilizers, humectants, pH-adjustors, synergists, and if desired, crosslinking agents may be added to make the preparation of the invention.
Confirmation of xcex1-form crystals of indomethacin in the preparation can be performed by visual inspection with a polarizing microscope which will be shown later in a Test Example, infrared analysis, X-ray analysis, differential thermal analysis, and a combination of any of them (N. Kananiwa, Seiyaku Kojo, 5, 9, 738-741, 1985).